Title: APOE as a modifier of prion-like spread in dementia Abstract: The overall objective of this multidisciplinary project is to test the hypothesis that relative to APOE2 or APOE3, APOE4 facilitates the seeding and spread of misfolded A? and tau. Inheritance of an APOE4 allele increases the risk of developing Alzheimer's disease (AD) dramatically. Most studies suggest that the primary mechanism by which APOE genotype modulates the risk for AD is by influencing the deposition of A? peptide. However, there are studies that suggest APOE may also directly modulate the phosphorylation and misfolding of tau. Somewhat surprisingly, although the first descriptions of A? seeding in mice were reported more than 10 years ago and various human APOE models have been available for many years, there have been no studies of how APOE genotype may modulate seeding or spread of misfolded A?. Similarly, there has been no study of how APOE genotype may influence the spread of misfolded tau. We now propose three Aims to conduct a thorough and systematic assessment of how different isoforms of human APOE impact the prion-like seeding and spread of misfolded A? and tau. A component of our study will also asess whether different APOE isoforms may interact with these aggregating proteins to produce distinct strains of misfolded A? or tau. Aim 1 will determine the relative ability of APOE2, APOE3 and APOE4 to support the seeding of A? pathology, the spread of A? aggregates within the brain, and whether APOE isoforms modulates the strain characteristics of the seeded A? aggregates. Aim 2 will determine whether APOE genotype influences the spread of CNS tau pathology, and whether any observed influence in spread is potentially due to the emergence of distinct strains of misfolded tau. Aim 3 will examine whether APOE isoforms may differentially modulate A?-induced misfolding of tau. Collectively, these studies will produce a unique repertoire of animal models and provide the first assessment of whether different human APOE isoforms may be influencing that pathogenesis of AD by modulating the prion-like seeding or spread of misfolded A? and tau.